Method for preparing quinoline derivative

Abstract

The invention relates to the field of organic synthesis, and discloses a method for preparing a quinoline derivative, which is characterized in that an enaminone compound and an N-phenylglycine ester compound are subjected to heating reaction in a solvent in the presence of an oxidizing agent to generate the quinoline derivative. According to the method, the dependence of a traditional method on a metal catalyst or complex multi-step conversion is abandoned, an additional activation step on an intermediate in the traditional method is avoided, the cost is remarkably reduced, the metal residue risk is eliminated, the green chemical requirement is met, and the problem that the tolerance of functional groups is limited is solved.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and more particularly to a method for preparing quinoline derivatives. Background Art

[0002] As important nitrogen-containing heterocyclic compounds, quinoline and its derivatives have irreplaceable application value in the design of active drug molecules, the development of functional materials and the total synthesis of natural products. In recent years, quinoline compounds with multiple carbonyl substitutions have become the focus of research in the development of drug lead compounds due to their unique electronic properties and structural modifiability. In the prior art, the synthesis of 2,3-dicarbonylquinoline has made significant progress. Typical methods include: three-component reaction under iodine / DMSO catalytic system: using cyclization reaction of acetophenone, aromatic amine and enaminones under redox neutral conditions, the construction of 2,3-benzoylated quinoline is achieved through acyl imine-iodine complex intermediates. Although this method has good atom economy, it is limited by a specific catalytic system, the scope of application of substrates is narrow, and it is difficult to achieve asymmetric dicarbonyl substitution. Photocatalytic activation strategy: Precursors such as ethyl bromodifluoroacetate are activated through a visible light-induced redox process, and a multi-component tandem reaction with enaminones is performed to generate 2,3-diester quinoline. Although this technology has expanded the types of reactions, it requires precious metal photocatalysts and has the problem of controlling side reactions. It is worth noting that the existing methods all focus on the 2,3-dicarbonyl substitution pattern, while the synthesis of 2,4-dicarbonylquinoline with different substitution patterns is still blank. Especially in the field of cross-dehydrogenative coupling (CDC) reaction, the traditional method based on the single electron transfer (SET) mechanism to activate N-phenylglycine ester generally has the following technical bottlenecks: (1) Oxidation control problem: conventional strong oxidation systems are prone to excessive oxidation of α-amino radicals to generate iminium ion intermediates, which have an electron repulsion effect with electron-deficient enaminones, severely inhibiting effective coupling; (2) Reaction path limitation: the existing mechanism relies on the electrophilic properties of iminium ions, but this property produces a thermodynamically unfavorable electron mismatch with the electron-deficient properties of enaminones, resulting in low reaction efficiency; (3) Intermediate stability defects: the carbon radical intermediates generated by traditional methods have a short lifetime, making it difficult to achieve an effective radical-radical coupling process. Based on the above technical status, the core issues to be solved in this field include: how to develop a new oxidation regulation system to achieve N-phenylglycine ester C (sp 3 )-H bond with enaminoketone C(sp 2 )-H bond synergistic activation; how to establish an effective free radical stabilization mechanism to prolong the lifetime of key carbon-centered free radicals and promote their effective collision and coupling with electron-deficient enaminone free radical species; how to design a simple and efficient synthetic route to avoid the multi-step intermediate transformation process and achieve a one-step construction of 2,4-dicarbonylquinoline. Summary of the Invention

[0003] To solve the above technical problems in the prior art, a method for preparing quinoline derivatives of the present invention includes the following steps: heating and reacting an enaminone compound with an N-phenylglycine ester compound in the presence of an oxidant in a solvent to form a quinoline derivative; wherein,

[0004] The structure of the enaminone compound is shown in Formula I:

[0005]

[0006] wherein: R 1 is selected from aryl, substituted aryl, heteroaryl, cyclopropyl or halogen;

[0007] The structure of the N-phenylglycine ester compound is shown in Formula II:

[0008]

[0009] wherein, R 2 is selected from alkyl, aryl, substituted aryl or heteroaryl.

[0010] The oxidant is selected from one or more of tert-butyl hydroperoxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, benzoyl peroxide, potassium permanganate, di-tert-butyl peroxide, diacetoxyiodobenzene, o-iodoxybenzoic acid, Dess-Martin oxidant, N-bromosuccinimide, potassium persulfate.

[0011] The reaction temperature of the method is 50 - 100 °C.

[0012] The molar ratio of the reaction is enaminone compound:N-phenylglycine ester compound:oxidant = 1:1:(1.5 - 3), and the reaction time is 1 - 3 hours.

[0013] The molar ratio of the reaction is enaminone compound:N-phenylglycine ester compound:oxidant = 1:1:2, and the reaction time is 1.5 hours.

[0014] The solvent is acetone, 1,4-dioxane, ethanol, 1,2-dichloroethane.

[0015] The present invention provides a quinoline derivative prepared by the above method, and its structure is shown in Formula (III):

[0016]

[0017] In Formula (III), R 1 is selected from aryl, substituted aryl, heteroaryl, cyclopropyl or halogen; R 2 is selected from alkyl, aryl, substituted aryl or heteroaryl.

[0018] The quinoline derivative described above is a 2,3-dicarbonyl quinoline derivative.

[0019] The quinoline derivative is any one of the following structures:

[0020]

[0021] The present invention provides a pharmaceutical intermediate or functional material, which contains the quinoline derivative described above.

[0022] The present invention has the following beneficial effects compared with the prior art:

[0023] In the present invention, by heating and reacting an enaminone compound with an N-phenylglycine ester compound in the presence of an oxidant in a solvent to generate a quinoline derivative, the dependence on metal catalysts or complex multi-step conversions in the traditional method is abandoned. The direct cross-dehydrogenative coupling of C(sp 2 )-H / C(sp 3 )-H can be achieved in only one step, avoiding the additional activation steps of intermediates in the traditional method, significantly reducing costs and eliminating the risk of metal residues, meeting the requirements of green chemistry; the reaction conditions of this application are mild (90 °C, 1.5 hours), the solvent system is simple, the operation is convenient and in line with the concept of green chemistry.

[0024] On the other hand, the method of the present invention effectively inhibits the over-oxidation of α-amino radicals in N-phenylglycine esters, stabilizes the key carbon-centered radicals, and promotes their coupling reaction with electron-deficient enaminones. Compared with the traditional iodine / DMSO or photocatalytic system, this system precisely regulates the radical process through a single-electron transfer mechanism, solves the problem of electron incompatibility, and significantly improves the reaction activity.

[0025] In addition, the method of the present invention has successfully synthesized 2,3-dicarbonyl quinoline derivatives with diverse structures, has strong substrate compatibility, and can tolerate electron-withdrawing groups, electron-donating groups, heterocyclic substituents, and substituents with large steric hindrance. In addition, the present invention has realized for the first time the direct radical coupling of electron-deficient enaminones with N-phenylglycine esters, filling the gap in the field of 2,3-dicarbonyl quinoline synthesis. Description of the Drawings

[0026] Figure 1 is the X-ray crystal structure of compound 3a in the present invention;

[0027] Figure 2 is the crystal data and structure refinement of compound 3a in the present invention;

[0028] Figure 3 is of compound 3a in the present invention 11H-NMR (400 MHz, CDCl3) spectrum;

[0029] Figure 4 is that of compound 3a in the present invention 13 13C-NMR (100 MHz, CDCl3) spectrum;

[0030] Figure 5 is the 1H-NMR (400 MHz, CDCl3) spectrum of compound 3b in the present invention;

[0031] Figure 6 is that of compound 3b in the present invention 13 13C-NMR (100 MHz, CDCl3) spectrum;

[0032] Figure 7 is that of compound 3c in the present invention 1 1H-NMR (400 MHz, CDCl3) spectrum;

[0033] Figure 8 is that of compound 3c in the present invention 13 13C-NMR (100 MHz, CDCl3) spectrum. Detailed implementation manners

[0034] To make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be described below through specific examples shown in the attached drawings. However, it should be understood that these descriptions are only exemplary and are not intended to limit the scope of the present invention. In addition, in the following descriptions, the descriptions of well-known structures and technologies are omitted to avoid unnecessarily confusing the concepts of the present invention.

[0035] Example 1

[0036] Enaminone 1a (0.2 mmol, accurately weighed) and N-phenylglycine ethyl ester 2a (0.2 mmol, accurately weighed) were added to a dry reaction flask, and acetonitrile (2.0 mL, dehydrated by molecular sieve) was added. Under stirring conditions, potassium persulfate (3.0 equivalents, 0.6 mmol) was added in batches. The reaction system was sealed and heated to 90 °C, and the reaction was continuously stirred for 1.5 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by reduced pressure concentration. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient ratio 10:1 to 5:1) to obtain the target product 3a, which was a white solid with a separation yield of 82% (calculated based on 1a).

[0037] Example 2

[0038] Under the conditions described in Example 1, the reaction time was adjusted to 0.5 h and 2.5 h respectively. The results showed that: 0.5 h: The yield of product 3a was 52% (Comparative Example 4-1), indicating that the reaction was not complete.

[0039] 2.5 h: The yield of product 3a was 78% (Comparative Example 4-2), which was close to the yield (82%) at 1.5 h, proving that 1.5 h was the optimal duration.

[0040] Example 3

[0041] Under the conditions described in Example 1, the amount of potassium persulfate was adjusted:

[0042] 1.0 equivalent: The yield of product 3a was 35% (Comparative Example 5-1), and the insufficient oxidant led to incomplete reaction.

[0043] 4.0 equivalents: The yield of product 3a was 84% (Comparative Example 5-2), and there was no significant difference in the effect compared with 3.0 equivalents. It was determined that 3.0 equivalents was an economical and efficient choice.

[0044] Example 4

[0045] Under the conditions described in Example 1, the molar ratio of enaminone 1a to 2a was adjusted:

[0046] 1:1.5 (1a:2a): The yield of product 3a decreased to 68% (Comparative Example 6-1), and the excessive 2a did not improve the efficiency.

[0047] 1:0.8 (1a:2a): The yield of product 3a further decreased to 47% (Comparative Example 6-2), proving that 1:1 was the optimal ratio.

[0048] Example 5

[0049] Under the conditions described in Example 1, acetonitrile was replaced with other solvents:

[0050] Tetrahydrofuran (THF): The yield of product 3a was 28% (Comparative Example 7-1).

[0051] N,N-Dimethylformamide (DMF): The yield of product 3a was 19% (Comparative Example 7-2).

[0052] Toluene: The yield of product 3a was 12% (Comparative Example 7-3).

[0053] Acetonitrile is irreplaceable for the high efficiency of the reaction.

[0054] Oxidant specificity: Potassium persulfate can significantly improve the yield (Table 1) compared to other oxidants (such as TBHP, DDQ, IBX, etc.). Temperature dependence: The yield drops sharply when the temperature is below 90 °C (Table 1), indicating that temperature is crucial for radical generation. Solvent effect: Acetonitrile can stabilize the transition state, which is superior to other solvents (Table 1).

[0055]

[0056] Preparation of substrate enaminone 1 Synthesis steps of aryl enaminones:

[0057]

[0058] The synthesized aryl enaminones are as follows in the table:

[0059]

[0060]

[0061] In a round-bottom flask equipped with a magnetic stir bar, add ketone S1 (10.0 mmol, 1.0 equiv) and 1,1-dimethoxy-N,N-dimethylmethanamine S2 (20.0 mmol, 2 equiv), using toluene (20 mL) as the solvent. Stir the mixture overnight in an oil bath at 110 °C. After the reaction is complete, extract the reaction mixture with ethyl acetate and dry it over anhydrous sodium sulfate. Subsequently, concentrate the reaction mixture under reduced pressure and purify the residue by column chromatography using a mixed solvent of petroleum ether and ethyl acetate (volume ratio 1:1) to obtain the corresponding aryl enaminones 1a - 1q.

[0062] Synthesis steps of arylalkyl enaminones:

[0063]

[0064] The synthesized arylalkyl enaminones are as follows in the table:

[0065]

[0066] In a round-bottom flask equipped with a magnetic stir bar, add ketone S3 (5.0 mmol, 1.0 equiv) and 1,1-dimethoxy-N,N-dimethylmethanamine S2 (50.0 mmol, 10.0 equiv). Stir the mixture overnight in an oil bath at 110 °C. After the reaction is completed, remove the solvent under vacuum conditions, and then purify the residue by column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio 1:1) to obtain the corresponding alkyl enaminones 1f and 1r.

[0067] Preparation of glycine derivatives:

[0068] Preparation of N-glycine ethyl ester:

[0069]

[0070] In a 100 mL round-bottom flask, an appropriate amount of aniline S5 (10 mmol, 1.0 eq) was dissolved in anhydrous ethanol (50 mL). Subsequently, ethyl bromoacetate S4 (10 mmol, 1.0 eq) was added dropwise. The mixture was heated to 70 °C and refluxed for 10 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the mixture was extracted with ethyl acetate and the precipitate was filtered. The filtrate was concentrated under vacuum to obtain products 2a - 2i.

[0071] The synthesized glycine derivatives are shown in the following table:

[0072]

[0073] Preparation of α - aminoacetophenone

[0074]

[0075] A mixture of aniline S7 (1 mmol, 1.0 eq) and 2 - bromoacetophenone compound S6 (1.2 mmol, 1.2 eq) was dissolved in 10 mL of methanol. Then, sodium bicarbonate (1.5 mmol) was added to the solution and stirred at room temperature. After the reaction was completed (monitored by thin-layer chromatography (TLC)), the mixture was extracted with ethyl acetate (15 mL × 2). The organic layer was washed with water (15 mL × 2) and finally dried over anhydrous sodium sulfate. The organic layer was concentrated using a rotary evaporator and the crude product was purified by silica gel (200 - 300 mesh) column chromatography. The yellow solid product 1 - phenyl - 2 - (phenylamino)ethanone 2j - 2l was obtained.

[0076]

[0077] Preparation methods of compounds 3a - 3r and 4a - 4l

[0078]

[0079] Enaminone derivative 1 (0.2 mmol, 1.0 equiv), glycine derivative 2 (0.2 mmol, 1.0 equiv), and potassium persulfate (0.6 mmol, 3.0 equiv) were added to a 10.0 mL reaction tube containing 2.0 mL (0.1 M) acetonitrile (MeCN). The mixture was stirred in an oil bath maintained at 90 °C for 1.5 h, and the reaction progress was monitored by thin-layer chromatography. Subsequently, the reaction system was cooled to room temperature, the reaction was quenched with 10 mL of saturated sodium chloride solution, and then extracted three times with 20.0 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to obtain products 3a - 3r and 4a - 4l. The products were further characterized by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0080] Example 6 (The synthesis conditions of 3b - 3o are the same as those of 3a)

[0081] Compound 3b (p-chloro substitution): Using p-chloro enaminone 1b instead of 1a, the yield of product 3b was 58%.

[0082] Compound 3c (p-iodo substitution): Using p-iodo enaminone 1c instead of 1a, the yield of product 3c was 53%.

[0083] Compound 3d (electron-donating group): Using enaminone 1d containing an electron-donating group as the substrate, the yield of product 3d was 71%.

[0084] Compound 3e (electron-donating group): Using enaminone 1e substituted with other electron-donating groups as the substrate, the yield of product 3e was 72%.

[0085] Compound 3i (electron-withdrawing group): Using enaminone 1i containing an electron-withdrawing group as the substrate, the yield of product 3i was 46%.

[0086] Compound 3j (electron-withdrawing group): Using enaminone 1j substituted with other electron-withdrawing groups as the substrate, the yield of product 3j was 45% (Table 2).

[0087] Compound 3f (cyclopropane substitution): Using enaminone 1f containing a cyclopropane substitution as the substrate, the yield of product 3f was 57%, indicating that the reaction is tolerant to the ring strain structure.

[0088] Compound 3o (heterocyclic substitution): Using enaminone 1o containing a thiophene ring as the substrate, the yield of product 3o was 53%.

[0089] Example 7 (The synthesis method of 4a - 4i is the same as that of 3a)

[0090] Compound 4a (monosubstituted phenyl): Using N-phenylglycine ethyl ester 2a as the substrate, the yield of product 4a was 71%.

[0091] Compound 4b (disubstituted phenyl): Using glycine ester 2b containing disubstituted phenyl as the substrate, the yield of product 4b was 74%.

[0092] Compound 4d (p-chloro substitution): Using p-chloro-substituted N-phenylglycine ester 2d as the substrate, the yield of product 4d was 58%.

[0093] Compound 4f (m-methyl substitution): Using m-methyl-substituted glycine ester 2f as the substrate, the yield of product 4f was 73%.

[0094] Compound 4c (β-naphthyl): Using β-naphthyl-substituted glycine ester 2c as the substrate, the yield of product 4c was 60%.

[0095] Compound 4h (methyl ester): Using N-phenylglycine methyl ester 2h to replace the ethyl ester, the yield of product 4h was 75%.

[0096] Compound 4i (tert-butyl ester): Using N-phenylglycine tert-butyl ester 2i as the substrate, the yield of product 4i was 41%.

[0097] The above yields were calculated based on the molar amount of the enaminone substrate (1a or derivatives).

[0098] This application is compatible with electron-withdrawing groups (Cl, I), electron-donating groups (OCH3, CH3) and heterocyclic substituents on the aromatic ring of enaminone; the benzene ring substituents (monosubstituted, disubstituted, halogen, alkyl) and naphthyl derivatives of -N-aryl glycine ester can be efficiently transformed; it has adaptability to the ester group type (ethyl ester, methyl ester, tert-butyl ester), but the yield of tert-butyl ester is relatively low (41%).

[0099] Through the system verification of Examples 6-7, the reaction system of the present invention shows a wide range of substrate applicability and can efficiently synthesize 2,3-dicarbonyl quinoline derivatives with diverse substituents (yield 36%-84%). This method shows good tolerance to structurally complex substrates (such as cyclopropane, heterocycle) and different ester derivatives, and has significant industrial application potential.

[0100]

[0101] This application further broadens the substrate scope of this reaction. This method was successfully applied to enaminones containing an ester group, and 2,3-diester quinoline (3r) was obtained in a yield of 54%. In addition, this transformation reaction was able to synthesize 2,3-diketo quinoline aryl compounds (4j - 4l) with different substituents (m-methyl, m-chloro, m-isopropyl), and the yields were moderate to good (41% - 63%). The above experimental content demonstrates the excellent substrate generality of this reaction system. Under the conditions of the present invention, enaminone 1a (10.0 mmol) reacted with N-phenylglycine ester 2a to obtain 3a (1.5 g) in an isolated yield of 76%. Subsequently, we explored its synthetic application using 3a as a representative substrate. In ethanol, 3a reacted with hydrazine hydrate to obtain the pyridopyridazine derivative 5, which confirmed its potential in constructing complex heterocyclic skeletons. In addition, under acidic conditions, 3a underwent transesterification with methanol to generate the methyl ester derivative 6. These transformation reactions not only highlight the synthetic diversity of 3a but also establish its value as a general synthetic building block. The successful cyclization reaction and transesterification reaction together reveal the great potential of 3a in constructing various molecular structures, confirming its practical application value in chemical transformations. The reaction conditions for Path b were: 3a (0.5 mmol), N2H4·H2O (2 equivalents), ethanol (2 mL), reflux for 12 hours. The reaction conditions for Path c were: 3a (0.5 mmol), methanol (2 mL), HCl (1 equivalent), react at 70 °C for 12 hours.

[0102]

[0103] The present invention proposes an efficient potassium persulfate-mediated cross-dehydrogenative coupling strategy, which is specifically used to construct the 2,3-diketo quinoline skeleton with important synthetic value. This application abandons the dependence on metal catalysts or complex multi-step transformations in traditional methods and can achieve the direct cross-dehydrogenative coupling of C(sp 2 )-H / C(sp 3 )-H in only one step, avoiding the additional activation steps for intermediates in traditional methods, significantly reducing costs and eliminating the risk of metal residues, meeting the requirements of green chemistry; the reaction conditions of this application are mild, the solvent system is simple, the operation is convenient and in line with the concept of green chemistry.

[0104] On the other hand, the method described in the present invention can effectively inhibit the excessive oxidation of α-amino radicals in N-phenylglycine esters, stabilize the key carbon-centered radicals, and promote their coupling reactions with electron-deficient enaminones. Compared with traditional iodine / DMSO or photocatalytic systems, the present invention precisely regulates the radical process through a single-electron transfer mechanism, solves the problem of electron incompatibility, and significantly improves the reaction activity.

[0105] The method of the present invention successfully synthesized 2,3-dicarbonyl quinoline derivatives with diverse structures, having strong substrate compatibility and being tolerant to electron-withdrawing groups, electron-donating groups, heterocyclic substituents, and substituents with large steric hindrance. In addition, the present invention realized for the first time the direct radical coupling of electron-deficient enaminones and N-phenylglycine esters, filling the gap in the field of 2,3-dicarbonyl quinoline synthesis. By using its high oxidation potential, it can activate enaminones and N-glycine esters simultaneously in the reaction system. Through kinetic control, it can regulate the radical / radical coupling process between N-glycine derivatives and electron-deficient enaminones, thereby ensuring the smooth progress of the reaction and generating the target product in high yield.

[0106] The data of the compounds involved in the present invention are as follows:

[0107]

[0108] Ethyl3-benzoylquinoline-2-carboxylate

[0109] 49.3mg, 82%yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethylacetate=20 / 1, V / V).

[0110] 1 H NMR(400 MHz, Chloroform-d)δ8.35(d, J=8.8 Hz, 1H), 8.33(s, 1H), 7.94 - 7.86(m, 2H), 7.82(d, J=7.2 Hz, 2H), 7.72(t, J=7.0 Hz, 1H), 7.61(t, J=7.4 Hz, 1H), 7.48(t, J=7.6 Hz, 2H), 4.27(q, J=7.2 Hz, 2H), 1.20(t, J=7.2 Hz, 3H).

[0111] 13 C NMR(100 MHz, CDCl3)δ193.7, 164.2, 146.8, 146.4, 136.3, 136.0, 132.5, 132.1, 130.6, 129.5, 128.6, 128.3, 127.7, 127.1, 126.5, 61.6, 12.8.

[0112] HRMS(ESI)m / z: Calcd for C 19 H 16 NO3 + [M + H]+ :306.1125;found:306.1124.

[0113]

[0114] Ethyl 3-(4-chlorobenzoyl)quinoline-2-carboxylate

[0115] 40.4 mg,58%yield.White solid,(Flash column chromatography eluent,petroleumether / ethyl acetate=20 / 1,V / V).

[0116] 1 H NMR(400 MHz,Chloroform-d)δ8.36(d,J=8.6 Hz,1H),8.31(s,1H),7.93(d,J=8.8Hz,1H),7.91-7.88(m,1H),7.82(t,J=1.7 Hz,1H),7.74(t,J=7.0 Hz,1H),7.67-7.65(m,1H),7.58-7.55(m,1H),7.41(t,J=7.8 Hz,1H),4.32(q,J=7.2 Hz,2H),1.25(t,J=7.2 Hz,3H).

[0117] 13 C NMR(100 MHz,CDCl3)δ192.4,164.1,146.5,146.4,137.7,136.2,134.1,132.4,131.6,130.8,129.5,129.0,128.5,128.4,127.1,126.7,61.7,12.9.

[0118] HRMS(ESI)m / z:Calcd for C 19 H 15 ClNO3 + [M+H] + :340.0735;found:340.0733.

[0119]

[0120] Ethyl 3-(4-iodobenzoyl)quinoline-2-carboxylate

[0121] 32.5 mg, 51% yield. White solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0122] 1 H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 8.5 Hz, 1H), 8.30 (s, 1H), 7.94 - 7.87 (m, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0123] 13 C NMR (100 MHz, CDCl3) δ 193.0, 164.1, 146.5, 146.4, 137.0, 136.1, 135.4, 131.7, 130.8, 129.8, 129.5, 128.5, 127.1, 126.5, 61.7, 12.9.

[0124] HRMS (ESI) m / z: Calcd for C 19 H 15 INO3 + [M + H] + : 432.0091; found: 432.0090.

[0125]

[0126] Ethyl 3-(4-methylbenzoyl)quinoline-2-carboxylate

[0127] 45.3 mg, 65% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0128] 11H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 8.0 Hz, 1H), 8.31 (s, 1H), 7.91 (d, J = 8 Hz, 2H), 7.89 - 7.85 (m, 1H), 7.73 (d, J = 8.0 Hz, 3H), 7.28 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0129] 13 13C NMR (100 MHz, CDCl3) δ 193.3, 164.2, 146.4, 143.5, 136.1, 133.5, 132.3, 130.5, 129.5, 128.8, 128.4, 128.2, 127.1, 126.6, 61.5, 20.7, 12.8.

[0130] HRMS (ESI) m / z: Calcd for C 20 H 18 NO3 + [M + H] + : 320.1281; found: 320.1280.

[0131]

[0132] Ethyl 3-([1,1'-biphenyl]-4-carbonyl)quinoline-2-carboxylate

[0133] 44.7 mg, 72% yield. Yellow solid, (Flash column chromatography eluent, petroleumether / ethyl acetate = 20 / 1, V / V).

[0134] 1 1H NMR (400 MHz, Chloroform-d) δ 8.37 - 8.36 (m, 2H), 7.95 - 7.87 (m, 4H), 7.76 - 7.72 (m, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.65 - 7.62 (m, 2H), δ 7.48 (t, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 1H)., 4.32 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H).

[0135] 1313C NMR (100 MHz, CDCl3) δ 193.3, 164.3, 146.8, 146.4, 145.2, 138.7, 136.2, 134.7, 132.3, 130.6, 129.5, 129.2, 128.3, 128.0, 127.4, 127.1, 126.33, 126.29, 61.6, 12.8. HRMS (ESI) m / z: Calcd for C 25 H 20 NO3 + [M + H] + : 382.1438; found: 382.1436.

[0136]

[0137] Ethyl 3-(cyclopropanecarbonyl)quinoline-2-carboxylate

[0138] 42.6 mg, 57% yield. Yellow oil, (Flash column chromatography eluent, petroleum ether / ethyl acetate=15 / 1, V / V).

[0139] 1 1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.69 (t, J=7.5 Hz, 1H), 4.51 (q, J=7.2 Hz, 2H), 2.57 - 2.51 (m, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.38 - 1.34 (m, 2H), 1.18 - 1.37 (m, 2H).

[0140] 13 13C NMR (100 MHz, CDCl3) δ 200.3, 165.6, 148.1, 146.6, 135.8, 131.5, 130.9, 129.1, 127.8, 127.4, 126.2, 61.5, 19.1, 13.1, 11.7.

[0141] HRMS (ESI) m / z: Calcd for C 16 H 16 NO3 + [M + H] +: 270.1125; found: 270.1124.

[0142]

[0143] 3-(3 - Bromobenzoyl)quinoline-2-carboxylic acid ethyl ester

[0144] 25.6 mg, 36% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0145] 1 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 8.6 Hz, 1H), 8.31 (s, 1H), 7.97 (t, J = 1.8 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.91 - 7.88 (m, 1H), 7.76 - 7.69 (m, 3H), 7.35 (t, J = 7.8 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0146] 13 13C NMR (100 MHz, CDCl3) δ 193.3, 165.1, 147.5, 147.4, 138.9, 137.2, 136.3, 132.6, 132.3, 131.8, 130.6, 130.3, 129.5, 128.2, 127.6, 123.1, 62.8, 13.9.

[0147] HRMS (ESI) m / z: Calcd for C 19 H 15 BrNO3 + [M + H] + : 384.0230; found: 384.0229.

[0148]

[0149] 3-(2 - Naphthoyl)quinoline-2-carboxylic acid ethyl ester

[0150] 45.9 mg, 71% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0151] 1 1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.39 (d, J = 9.0 Hz, 1H), 8.13 (s, 1H), 8.08 - 8.06 (m, 1H), 7.97 - 7.89 (m, 4H), 7.83 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H).

[0152] 13 13C NMR (100 MHz, CDCl3) δ 193.7, 164.2, 146.9, 146.5, 136.4, 134.7, 133.5, 132.3, 131.3, 131.0, 130.6, 129.5, 128.6, 128.3, 127.84, 127.81, 127.1, 126.8, 126.6, 126.0, 123.5, 61.6, 12.8.

[0153] HRMS (ESI) m / z: Calcd for C 23 H 18 NO3 + [M + H] + : 356.1281; found: 356.1280.

[0154]

[0155] Ethyl 3-(4-nitrobenzoyl)quinoline-2-carboxylate

[0156] 27.3 mg, 46% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0157] 11H NMR (400 MHz, Chloroform-d) δ 8.63 - 8.62 (m, 1H), 8.47 - 8.44 (m, 1H), 8.39 (d, J = 9.0 Hz, 1H), 8.32 (s, 1H), 8.16 - 8.14 (m, 1H), 7.94 (t, J = 7.2 Hz, 2H), 7.77 (t, J = 6.6 Hz, 1H), 7.69 (t, J = 5.8 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0158] 13 13C NMR (100 MHz, CDCl3) δ 191.5, 164.1, 147.4, 146.6, 145.9, 137.7, 136.0, 133.8, 131.3, 131.0, 129.7, 129.0, 128.8, 127.1, 126.6, 126.5, 123.1, 61.9, 13.0.

[0159] HRMS (ESI) m / z: Calcd for C 19 H 15 N2O5 + [M + H] + : 351.0975; found: 351.0974.

[0160]

[0161] Ethyl 3-(4-(methylsulfonyl)benzoyl)quinoline-2-carboxylate

[0162] 23.6 mg, 45% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0163] 1 1H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J = 9.1 Hz, 1H), 8.20 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.07 - 8.04 (m, 3H), 7.99 - 7.97 (m, 3H), 4.33 (q, J = 7.2 Hz, 2H), 3.09 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0164] 13 13C NMR (100 MHz, CDCl3) δ 192.9, 164.9, 147.2, 146.1, 144.5, 140.9, 135.9, 135.7, 133.4, 132.1, 130.2, 130.1, 129.2, 128.6, 127.9, 124.3, 118.3, 63.7, 44.3, 14.0.

[0165] HRMS (ESI) m / z: Calcd for C 20 H 18 NO5S + [M + H] + : 384.0900; found: 384.0899.

[0166]

[0167] Ethyl 3-(4-(tert-butoxycarbonyl)benzoyl)quinoline-2-carboxylate

[0168] 49.3 mg, 63% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0169] 1 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 8.6 Hz, 1H), 8.32 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.94 - 7.91 (m, 1H), 7.91 - 7.88 (m, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.74 (t, J = 7.2 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.60 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H).

[0170] 13 13C NMR (100 MHz, CDCl3) δ 193.1, 164.1, 163.7, 146.5, 138.9, 136.3, 135.0, 131.8, 130.8, 129.5, 128.7, 128.5, 128.3, 127.1, 126.5, 80.9, 61.7, 27.1, 12.8.

[0171] HRMS(ESI) m / z: Calcd for C 24 H 24 NO5[M + H] + : 406.1649; found: 406.1648.

[0172]

[0173] Ethyl 3-(4-(methoxycarbonyl)benzoyl)quinoline-2-carboxylate

[0174] 32.1 mg, 53% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0175] 1 H NMR(400 MHz, Chloroform - d) δ 8.37(d, J=8.5 Hz, 1H), 8.34(s, 1H), 8.13(d, J=8.2 Hz, 2H), 7.93(t, J=7.2 Hz, 2H), 7.87(d, J=8.2 Hz, 2H), 7.75(t, J=7.5 Hz, 1H), 4.29(q, J=7.2 Hz, 2H), 3.96(s, 3H), 1.22(t, J=7.2 Hz, 3H).

[0176] 13 C NMR(100 MHz, CDCl3) δ 193.1, 165.1, 164.1, 146.5, 146.4, 139.3, 136.3, 133.1, 131.7, 130.8, 129.5, 128.9, 128.5, 128.4, 127.1, 126.5, 61.7, 51.6, 12.8.

[0177] HRMS(ESI) m / z: Calcd for C 21 H 18 NO5 + [M + H] + : 364.1179; found: 364.1179.

[0178]

[0179] Ethyl 3-(4-methoxybenzoyl)quinoline-2-carboxylate

[0180] 36.2 mg, 61% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0181] 1 H NMR (400 MHz, Chloroform-d) δ8.34 (d, J = 8.5 Hz, 1H), 8.30 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.71 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H).

[0182] 13 C NMR (100 MHz, CDCl3) δ192.4, 164.3, 162.9, 146.8, 146.3, 135.9, 132.5, 131.0, 130.4, 129.5, 129.0, 128.2, 127.0, 126.6, 112.9, 61.5, 54.6, 12.8.

[0183] HRMS (ESI) m / z: Calcd for C 20 H 18 NO4[M + H] + : 336.1230; found: 336.1228.

[0184]

[0185] Ethyl 3-(3,4-dimethoxybenzoyl)quinoline-2-carboxylate

[0186] 35.9 mg, 57% yield. Yellow oil, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0187] 11H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H), 7.92 - 7.86 (m, 2H), 7.72 (t, J = 7.2 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.19 - 7.17 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0188] 13 13C NMR (100 MHz, CDCl3) δ 192.4, 164.3, 152.7, 148.3, 146.8, 146.3, 136.1, 132.3, 130.5, 129.4, 129.2, 128.3, 127.0, 126.6, 124.5, 123.5, 109.6, 108.9, 61.6, 55.1, 12.9.

[0189] HRMS (ESI) m / z: Calcd for C 21 H 20 NO5 + [M + H] + : 366.1336; found: 366.1336.

[0190]

[0191] Ethyl 3-(benzo[d][1,3]dioxole-5-carbonyl)quinoline-2-carboxylate

[0192] 36.1 mg, 53% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0193] 11H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J = 8.5 Hz, 1H), 8.28 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.71 (t, J = 7 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.27 - 7.23 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.07 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0194] 13 13C NMR (100 MHz, CDCl3) δ 192.0, 164.2, 151.3, 147.4, 146.6, 146.3, 135.9, 132.4, 130.9, 130.5, 129.5, 128.3, 127.0, 126.5, 125.9, 107.8, 106.9, 101.1, 61.6, 12.9.

[0195] HRMS (ESI) m / z: Calcd for C 20 H 16 NO5 + [M + H] + : 350.1023; found: 350.1021.

[0196]

[0197] Ethyl 3-(furan-2-carbonyl)quinoline-2-carboxylate

[0198] 34.2 mg, 52% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0199] 11H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.77 - 7.69 (m, 1H), 7.66 - 7.64 (m, 1H), 7.19 - 7.17 (m, 1H), 6.61 - 6.59 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0200] 13 13C NMR (100 MHz, CDCl3) δ 180.7, 164.3, 146.3, 136.7, 130.9, 130.8, 129.44, 129.38, 128.3, 128.2, 127.3, 127.2, 126.5, 118.5, 111.7, 61.6, 12.9。

[0201] HRMS (ESI) m / z: Calcd for C 17 H 14 NO4 + [M + H] + : 296.0917; found: 296.0915.

[0202]

[0203] Ethyl 3-(thiophene-2-carbonyl)quinoline-2-carboxylate

[0204] 31.3 mg, 67% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0205] 1 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 4.9 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 3.8 Hz, 1H), 7.13 (t, J = 4.7 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0206] 13 C NMR (100 MHz, CDCl3) δ 185.7, 164.2, 146.5, 143.2, 136.0, 134.1, 133.8, 131.7, 130.7, 129.5, 128.3, 127.3, 127.1, 126.4, 61.6, 12.8.

[0207] HRMS (ESI) m / z: Calcd for C 17 H 14 NO3S + [M + H] + : 312.0689; found: 312.0687.

[0208]

[0209]

[0210] Diethyl quinoline-2,3-dicarboxylate

[0211] 29.4 mg, 54% yield. Yellow oil, (Flash column chromatography eluent, petroleum ether / ethylacetate = 15 / 1, V / V).

[0212] 1 H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.69 - 7.66 (m, 1H), 4.53 (q, J = 7.2 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H).

[0213] 13 C NMR (100 MHz, CDCl3) δ 165.9, 164.1, 150.0, 147.0, 138.6, 131.3, 128.8, 127.6, 127.6, 126.0, 121.4, 61.4, 61.0, 13.2, 13.1.

[0214] HRMS (ESI) m / z: Calcd for C 15 H16 NO4 + [M+H] + :274.1074;found:274.1076.

[0215]

[0216] Ethyl 3-benzoyl-6-methylquinoline-2-carboxylate

[0217] 45.6 mg,65%yield.Yellow solid,(Flash column chromatography eluent,petroleumether / ethyl acetate=20 / 1,V / V).

[0218] 1 H NMR(400 MHz,Chloroform-d)δ8.24-8.22(m,2H),7.81(d,J=7.2 Hz,2H),7.72-7.69(m,1H),7.67(s,1H),7.61-7.57(m,1H),7.46(t,J=7.9 Hz,2H),4.26(q,J=7.2Hz,2H),2.59(s,3H),1.19(t,J=7.2 Hz,3H).

[0219] 13 C NMR(100 MHz,CDCl3)δ193.9,164.2,145.7,145.0,138.8,136.1,135.4,133.0,132.4,132.3,129.1,128.6,127.7,126.7,125.8,61.5,20.8,12.8.

[0220] HRMS(ESI)m / z:Calcd for C 20 H 18 NO3 + [M+H] + :320.1281;found:320.1280.

[0221]

[0222] Ethyl 3-benzoyl-5,7-dimethylquinoline-2-carboxylate

[0223] 47.1 mg, 71% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0224] 1 1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.96 (s, 1H), 7.82 - 7.79 (m, 2H), 7.60 - 7.56 (m, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.37 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.65 (s, 3H), 2.56 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H).

[0225] 13 13C NMR (100 MHz, CDCl3) δ 194.1, 164.3, 147.2, 146.1, 141.0, 136.3, 133.8, 132.7, 132.3, 131.1, 130.9, 128.5, 127.6, 126.5, 124.3, 61.4, 21.0, 17.5, 12.8.

[0226] HRMS (ESI) m / z: Calcd for C 21 H 20 NO3 + [M + H] + : 334.1438; found: 334.1439.

[0227]

[0228] Ethyl 3-benzoylbenzo[g]quinoline-2-carboxylate

[0229] 39.4 mg, 60% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 30 / 1, V / V).

[0230] 11H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.63 - 8.58 (m, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 8.01 - 7.98 (m, 1H), 7.86 - 7.83 (m, 2H), 7.75 - 7.72 (m, 2H), 7.64 - 7.58 (m, 1H), 7.48 (t, J = 7.9 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).

[0231] 13 13C NMR (100 MHz, CDCl3) δ 194.1, 164.1, 147.0, 145.6, 136.2, 132.7, 132.5, 132.2, 131.6, 130.8, 128.6, 128.0, 127.9, 127.8, 127.7, 127.0, 126.9, 125.0, 122.4, 61.6, 12.8.

[0232] HRMS (ESI) m / z: Calcd for C 23 H 18 NO3 + [M + H] + : 356.1281; found: 356.1283.

[0233]

[0234] Ethyl 3-benzoyl-6-chloroquinoline-2-carboxylate

[0235] 47.3 mg, 58% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0236] 1 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 9.0 Hz, 1H), 8.23 (s, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.82 - 7.79 (m, 3H), 7.63 - 7.60 (m, 1H), 7.48 (t, J = 7.8 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).

[0237] 13 C NMR (100 MHz, CDCl3) δ 193.2, 163.9, 146.9, 144.7, 135.1, 134.4, 133.1, 132.6, 131.6, 131.0, 128.6, 128.3, 127.8, 127.2, 125.7, 61.7, 13.1.

[0238] HRMS (ESI) m / z: Calcd for C 19 H 15 ClNO3 + [M + H] + : 340.0735; found: 340.0732.

[0239]

[0240] Ethyl 3-benzoyl-6-iodoquinoline-2-carboxylate

[0241] 34.5 mg, 65% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0242] 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 8.12 - 8.09 (m, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.80 - 7.78 (m, 2H), 7.64 - 7.59 (m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).

[0243] 13 C NMR (100 MHz, CDCl3): δ 193.2, 163.9, 147.1, 145.3, 139.4, 137.2, 135.8, 135.7, 134.8, 132.9, 132.6, 130.8, 128.6, 128.0, 127.8, 61.7, 12.8.

[0244] HRMS (ESI) m / z: Calcd for C 19 H 15 INO3+ [M+H] + :432.0091;found:432.0090.

[0245]

[0246] Ethyl 3-benzoyl-7-methylquinoline-2-carboxylate

[0247] 48.5 mg,73%yield.Yellow solid,(Flash column chromatography eluent,petroleumether / ethyl acetate=15 / 1,V / V).

[0248] 1 H NMR(400 MHz,Chloroform-d)δ8.28(s,1H),8.12(s,1H),7.84-7.78(m,2H),7.60(t,J=7.4 Hz,1H),7.54(d,J=7.0 Hz,2H),7.47(t,J=7.8 Hz,2H),4.26(q,J=7.2Hz,2H),2.62(s,3H),1.20(t,J=7.2 Hz,3H).

[0249] 13 C NMR(100 MHz,CDCl3)δ193.8,164.4,146.9,146.7,136.1,136.0,132.4,131.3,130.6,128.6,128.7,128.4,127.68,127.65,126.7,61.5,21.1,12.8.

[0250] HRMS(ESI)m / z:Calcd for C 20 H 18 NO3 + [M+H] + :320.1281;found:320.1280.

[0251]

[0252] Ethyl 3-benzoyl-7-chloroquinoline-2-carboxylate

[0253] 32.1 mg, 53% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0254] 1 1H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.32 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.69 - 7.66 (m, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H).

[0255] 13 13C NMR (100 MHz, CDCl3) δ 193.3, 163.9, 148.0, 146.7, 136.8, 136.1, 132.6, 132.2, 129.4, 129.2, 128.6, 128.4, 128.2, 127.8, 127.5, 61.7, 12.8.

[0256] HRMS (ESI) m / z: Calcd for C 19 H 15 ClNO3 + [M + H] + : 340.0735; found: 340.0737.

[0257]

[0258] Methyl 3-benzoylquinoline-2-carboxylate

[0259] 39.8 mg, 75% yield. Yellow oil, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0260] 11H NMR (600 MHz, Chloroform-d) δ 8.22 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.96 - 7.94 (m, 1H), 7.81 - 7.79 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 3H), 3.84 (s, 3H).

[0261] 13 13C NMR (150 MHz, CDCl3) δ 193.2, 164.3, 146.6, 144.9, 135.7, 135.0, 134.3, 133.2, 132.7, 130.96, 129.1, 128.6, 127.8, 127.7, 122.9, 52.3.

[0262] HRMS (ESI) m / z: Calcd for C 18 H 14 NO3 + [M + H] + : 292.0968; found: 292.0967.

[0263]

[0264] Tert-butyl 3-benzoylquinoline-2-carboxylate

[0265] 28.3 mg, 41% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0266] 1 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 8.6 Hz, 1H), 8.30 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.87 - 7.83 (m, 3H), 7.70 (t, J = 8.0 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.48 (t, J = 7.7 Hz, 2H), 1.30 (s, 9H).

[0267] 1313C NMR (100 MHz, CDCl3) δ 193.6, 162.9, 147.8, 146.5, 136.2, 136.1, 132.5, 131.8, 130.4, 129.5, 128.8, 128.0, 127.7, 127.0, 126.5, 83.0, 26.4.

[0268] HRMS (ESI) m / z: Calcd for C 21 H 20 NO3 + [M + H] + : 334.1438; found: 334.1437.

[0269]

[0270] (3-benzoylquinolin-2-yl)(p-tolyl)methanone

[0271] 34.2 mg, 63% yield. Yellow solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 15 / 1, V / V).

[0272] 1 1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.87 (t, J = 7.4 Hz, 3H), 7.72 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 2.43 (s, 3H).

[0273] 13 13C NMR (100 MHz, CDCl3) δ 195.1, 193.4, 156.6, 146.8, 144.5, 137.9, 136.8, 133.4, 133.2, 133.0, 131.8, 131.1, 130.2, 130.1, 129.1, 128.9, 128.6, 128.4, 126.6, 21.9.

[0274] HRMS (ESI) m / z: Calcd for C 24 H 18 NO2+ [M+H] + : 352.1332; found: 352.1331.

[0275]

[0276] (3-benzoylquinolin-2-yl)(4-chlorophenyl)methanone

[0277] 25.2 mg, 41% yield. White solid, (Flash column chromatography eluent, petroleum ether / ethyl acetate=15 / 1, V / V).

[0278] 1 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 7.96 - 7.91 (m, 1H), 7.88 (t, J=7.0 Hz, 3H), 7.81 (d, J=8.5 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.61 (t, J=6.8 Hz, 1H), 7.50 - 7.42 (m, 3H).

[0279] 13 13C NMR (100 MHz, CDCl3) δ 194.0, 191.4, 154.9, 145.7, 139.0, 137.1, 135.6, 133.0, 132.6, 131.9, 131.3, 130.9, 129.1, 129.0, 128.11, 128.08, 128.0, 127.68, 127.65.

[0280] HRMS (ESI) m / z: Calcd for C 23 H 15 ClNO2 + [M+H] + : 372.0786; found: 372.0785.

[0281]

[0282] (6-isopropylquinoline-2,3-diyl)bis(phenylmethanone)

[0283] 36.8 mg, 61% yield. Yellow oil, (Flash column chromatography eluent, petroleum ether / ethyl acetate = 20 / 1, V / V).

[0284] 1 1H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.10 - 8.06 (m, 2H), 7.89 - 7.86 (m, 2H), 7.81 - 7.78 (m, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.48 - 7.43 (m, 4H), 3.19 - 3.12 (m, 1H), 1.38 (d, J = 6.9 Hz, 6H).

[0285] 13 13C NMR (100 MHz, CDCl3) δ 194.2, 192.7, 154.5, 149.0, 144.7, 136.6, 135.8, 134.7, 132.41, 132.35, 131.9, 130.9, 129.9, 129.0, 128.9, 127.7, 127.6, 127.3, 123.5, 33.2, 22.7.

[0286] HRMS (ESI) m / z: Calcd for C 26 H 22 NO2 + [M + H] + : 380.1645; found: 380.1646.

[0287]

[0288] 1-phenylpyridazino[4,5-b]quinolin-4(3H)-one

[0289] 31.4 mg, 58% yield. Yellow solid, (Directly extract).

[0290] 11H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.79 (s, 1H), 8.30 (t, J = 7.2 Hz, 2H), 8.03 (t, J = 7.6 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.71 - 7.69 (m, 2H), 7.63 - 7.57 (m, 3H).

[0291] 13 13C NMR (100 MHz, DMSO) δ 158.8, 149.4, 146.9, 143.7, 137.0, 135.2, 133.3, 130.1, 130.0, 129.9, 129.7, 129.5, 129.21, 129.16, 123.2.

[0292] HRMS (ESI) m / z: Calcd for C 17 H 12 N3O1 + [M + H] + : 274.0975; found: 274.0974.

Claims

1. A method for preparing quinoline derivatives, characterized in that, It includes the following steps: heating and reacting an enaminone compound with an N-phenylglycine ester compound in a solvent in the presence of an oxidant to produce a quinoline derivative; wherein, The structure of the enaminone compound is shown in Formula I: Wherein: R 1 is selected from aryl, substituted aryl, heteroaryl, cyclopropyl or halogen; The structure of the N-phenylglycine ester compound is shown in Formula II: wherein, R 2 is selected from alkyl, aryl, substituted aryl or heteroaryl.

2. The method for preparing a quinoline derivative according to claim 1, characterized in that, The oxidant is selected from one or more of tert-butyl hydroperoxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, benzoyl peroxide, potassium permanganate, di-tert-butyl peroxide, diacetoxyiodobenzene, o-iodoxybenzoic acid, Dess-Martin oxidant, N-bromosuccinimide, potassium persulfate.

3. The method for preparing a quinoline derivative according to claim 1, characterized in that, The reaction temperature of the method is 50-100 °C.

4. The method for preparing a quinoline derivative according to claim 1, characterized in that, The molar ratio of the reaction is enaminone compound: N-phenylglycine ester compound: oxidant = 1:1: (1.5-3), and the reaction time is 1-3 hours.

5. The method for preparing a quinoline derivative according to claim 4, characterized in that, The molar ratio of the reaction is enaminone compound: N-phenylglycine ester compound: oxidant = 1:1:2, and the reaction time is 1.5 hours.

6. The method for preparing a quinoline derivative according to claim 5, characterized in that, The solvent is acetone, 1,4-dioxane, ethanol, 1,2-dichloroethane.

7. A quinoline derivative prepared by the method according to any one of claims 1-6, and its structure is shown in Formula (III): R in formula (III) 1 is selected from aryl, substituted aryl, heteroaryl, cyclopropyl or halogen; R 2 is selected from alkyl, aryl, substituted aryl or heteroaryl.

8. The quinoline derivative according to claim 7, wherein, The quinoline derivative is a 2,3-dicarbonyl quinoline derivative.

9. The quinoline derivative according to claim 7, characterized in that, The quinoline derivative has any of the following structures:

10. A pharmaceutical intermediate or functional material, comprising the quinoline derivative according to claim 8 or 9.

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